Biodegradable polymers have been used as surgical sutures, wound dressings, and as drug delivery systems. Among them, polylactide (PLA), polyglycolide (PGA) and their copolymers (PLGA) have attracted the most attention. One example of a biodegradable polymeric drug delivery system is a system wherein a drug is contained in a biodegradable polymer matrix that is surgically implanted, which is a big disadvantage. In the form of injectable drug delivery systems, polymeric microspheres and nanospheres are known in the art. Commercially available drug delivery formulations based on PLGA microspheres include Lupron Depot® and Nutropin Depot®. Microsphere and nanosphere systems have disadvantages in that they require special and complex preparation methods. Unfortunately, manufacturing microsphere and nanosphere dosage forms requires use of toxic or dangerous solvents (e.g., methylene chloride, ethyl acetate) and elaborate procedures (e.g., double emulsions, or cryogenic spraying techniques). The batch size is usually small and the cost is high. In addition, since PLGA biodegradable polymers used can only be dissolved in organic solvents their preparation requires the use of such solvents which are foreign and harmful to the human body, and cannot be completely removed during manufacture by any known method. Furthermore, some drugs such as peptides and proteins may lose their pharmacological activity after contact with organic solvents.
An improvement to the aforementioned drug delivery systems is an in situ formed depot based on PLGA as disclosed in U.S. Pat. No. 5,599,552. In that system, PLGA is dissolved in water-soluble organic solvent(s), such as N-methyl-2-pyrrolidone, and the drug is either suspended or dissolved in this polymeric solution. The solution can be injected subcutaneously to form an in situ depot to trap the drug in the polymer that precipitates as the organic solvent diffuses away. However, the drawback is the requirement for an organic solvent that is used to dissolve the biodegradable PLGA polymer. Organic solvents, such as N-methyl-2-pyrrolidone, are foreign to the human body and can cause unwanted side effects both acutely and chronically.
U.S. Pat. No. 5,543,158 discloses nanoparticles or microparticles formed from a water-insoluble block copolymer consisting essentially of poly(alkylene glycol) and poly(lactic acid). The molecular weight of the block copolymer is high and the copolymer is insoluble in water. In the nanoparticle or microparticle, the biodegradable moieties of the copolymer are in the core of the nanoparticle or microparticle and the poly(alkylene glycol) moieties are on the surface of the nanoparticle or microparticle in an amount effective enough to decrease uptake of the nanoparticle or microparticle by the reticuloendothelial system. Nanoparticles are prepared by dissolving the block copolymer and drug in an organic solvent, forming an o/w emulsion by sonication or stirring, and collecting the nanoparticles containing the drug following precipitation.
Currently there are few synthetic or natural polymeric materials that can be used for the controlled delivery of drugs, including peptide and protein drugs, because of strict regulatory compliance requirements such as biocompatibility, low toxicity, having a clearly defined degradation pathway, and safety of the polymers and degradation products. The most widely investigated and advanced biodegradable polymers in regard to available toxicological and clinical data are the aliphatic poly(α-hydroxy acids), such as poly(D-, L-, or D, L-lactic acid) (PLA), poly(glycolic acid) (PGA) and their copolymers (PLGA). These polymers are commercially available and are presently used as bioresorbable sutures and in biodegradable microsphere drug delivery systems. FDA-approved microsphere systems for controlled release of leuprolide acetate (Lupron Depot™) and human growth hormone (Nutropin Depot™) are based on PLGA copolymers. Based on this history of use, PLGA copolymers have been the materials of choice in the initial design of parenteral controlled release drug delivery systems using a biodegradable carrier.
Even though there has been some limited success, biodegradable block copolymers that are based on biodegradable polyester or poly(ortho ester) and polyethylene glycol (PEG) blocks, when used as drug carriers, present problems that are associated with their physicochemical properties and attendant methods of fabrication. For example, biodegradable block copolymers are, by design, not stable in aqueous environments although shelf-lives of several years can be achieved when they are stored frozen. However, elimination of cold storage requirements would be advantageous in most instances. It is also desirable to gain further advantages related to rapid dissolution of neat block copolymers into aqueous vehicles at normal or ambient room temperature conditions. Rapid dissolution of the block copolymers permits reconstitution at time-of-use to occur, which in turn permits room temperature storage of neat block copolymers. Known water soluble block copolymers are slow to dissolve in water, often requiring several hours for complete dissolution to occur. Compositions that show accelerated dissolution kinetics are desired.
Some drugs, such as proteins, are stable in aqueous solutions for only short periods. To compensate for this short-term stability, these drugs are commonly formulated as dry cakes and powders that can be stored under water-free conditions for much longer periods. Immediately prior to administration the dry cake or powder is reconstituted with an aqueous vehicle. Thus the situation is frequently encountered where it is desirable to have both the drug and the block copolymer drug delivery system formulated in reconstitutable forms. To be facile, it is critical that reconstitution, i.e., dissolution of the block copolymers and drug be completed in a short period.
U.S. Pat. No. 5,384,333 discloses an injectable drug delivery composition in which a pharmacologically active substance is contained in a copolymer comprising a hydrophilic part and a hydrophobic part. However, the composition has to be heated to a relatively high temperature such as 38° C. to 52° C., immediately before use and it is difficult to uniformly distribute the drug in the polymeric composition. U.S. Pat. No. 5,612,052 discloses a block copolymer composition that when contacted with water forms a hydrogel. However, the drug incorporated in this composition is rapidly released. U.S. Pat. No. 5,599,552 discloses a composition wherein a water-insoluble biodegradable thermoplastic polymer is dissolved in a water-miscible organic solvent, and the resulting composition can be implanted where it then undergoes a phase transition when in contact with water or body fluids. However, the drawback is that it is difficult to use because a mono-molecular organic solvent is used to dissolve the biodegradable thermoplastic polymer. Most mono-organic solvents, such as N-methyl-2-pyrrolidone, ethyl lactate, dimethylsulfoxide, etc., cause side effects such as cell dehydration and tissue necrosis, etc. and they may also cause severe pain at the application sites.
U.S. Pat. No. 5,607,686 discloses a liquid polymeric composition prepared by mixing a hydrophilic liquid polymer, instead of a mono-molecular organic solvent, with a water-insoluble hydrophobic polymer. When contacted with water the composition undergoes a phase transition and forms an implant and thus it does not cause a the rapid volume reduction and it has no special side effects due to the good cyto-compatibility of the low molecular weight polyethylene oxide. However, the water-insoluble hydrophobic polymers used are not biodegradable. In addition, the preparation of the composition requires heating to about 80° C. in order to achieve uniform mixing of the water-insoluble hydrophobic polymer and the hydrophilic liquid polymer. Therefore, this system may be suitable to use for adherence prevention and wound protection without any physiologically active substance, but it is not suitable for delivery of physiologically active substances, particularly peptide or protein medicines because peptide and protein medicines lose their activities at high temperatures. Furthermore, protein medicines are water soluble, thus it is very difficult to uniformly incorporate them into the composition. In addition, it is not disclosed in this patent how the drugs or physiologically active substances can be uniformly incorporated in the polymeric composition. Particularly, although polylactide, polyglycolide and their copolymers can be mixed with polyethylene glycol at high temperatures of 80° C. in order to obtain a uniform composition, the composition undergoes phase separation when it stands for a long period of time due the lowered affinity of the polylactide, the polyglycolide or their copolymers with polyethylene glycol. Therefore, it is very difficult to maintain a uniform composition.
Sterilization steps are necessary in the preparation of implant formulations. Existing sterilization methods are unsuitable for sustained drug delivery formulations due to properties of the implant compositions or because the methods are uneconomical or too complicated. For example, it is almost impossible to prepare a uniform solution by mixing a drug, a water-insoluble biodegradable polymer and a hydrophilic polymer. Therefore, the composition cannot be sterilized by simple methods such as membrane filtration. Furthermore, although the formulation may be prepared under sterilize conditions, such methods are very expensive to the extent that the practicability of the preparation may be lowered.
Therefore, there is a need for a biodegradable drug delivery composition that is a flowable liquid or can be rapidly reconstituted in an aqueous vehicle to afford a homogeneous true solution or uniform colloidal system in order to be easily prepared and administered to provide improved drug delivery. Accordingly, the present invention represents improved drug delivery compositions that minimize or are free of the problems mentioned above.